Polycystic kidney disease (PKD) is characterized by kidney cysts and may account for 5-8% of all end stage renal disease in the United States. The autosomal dominant form of PKD is due to inherited mutation of either PKD1 or PKD2 and cyst formation is believed to begin with "second step" autosomal mutations that occur in kidney epithelial cells. The relationship between second step autosomal mutation and kidney cyst development in two mouse models of autosomal dominant PKD is the focus of this exploratory R21 application. The major hypothesis to be tested is that environmental and genetic approaches that increase somatic mutations in renal epithelial cells will proportionally increase cyst formation in mice heterozygous for Pkd1 or Pkd2. Two specific aims are offered. The first will use ionizing radiation to induce mutations in the right kidneys of mice whose left kidneys will be shielded from exposure. Cyst formation will then be quantified with histological methods in the exposed and shielded kidneys as a function of time after exposure. By controlling mutation induction with ionizing radiation exposure the amount of time necessary for a somatic mutational event to translate into a kidney cyst can be determined. The second aim will use mismatch repair deficiency to increase autosomal mutations 10-fold or greater in the kidney cells. The presence of mononucleotide runs in the coding sequence of Pkd1, but not in Pkd2, is predicted to make the Pkd1 gene significantly more mutable in the mismatch repair deficient background, and thereby demonstrate a potential role for gene structure in cyst formation. Immunohistochemistry will be used in both specific aims to provide evidence that the types of mutations present in the cells surrounding the kidney cysts are consistent with the mutational approaches taken because the presence or absence of PKD protein will reflect small and large mutational events, respectively. Successful completion of the proposed experiments will provide basic information about the etiology and pathogenesis of PKD by directly demonstrating quantitative and temporal relationships between autosomal mutation and cyst formation. [unreadable] [unreadable] [unreadable]